University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, Alberta T6G 2N8, Canada.
J Pharm Pharm Sci. 2009;12(3):337-45. doi: 10.18433/j3d012.
Inflammation in forms of rheumatoid and experimental arthritis cause not only joint pain but also excessive cardiovascular mortality. The condition also reduces response to calcium channel and beta-adrenergic (beta1-AR) antagonists. For calcium channel inhibitors, the reduced response is shown to be due to the reduced expression of target proteins. Hydroxymethylglutaryl CoA reductase inhibitors (statins) restore response to propranolol and verapamil. We tested the effect of adjuvant arthritis on the norepinephrine (NE) transporter (NET) density since altered sympathetic nervous system innervation has been observed in rheumatoid arthritis.
Male Sprague-Dawley rats were divided into the following groups: Healthy/Placebo, Healthy/Statin, Pre-AA/Placebo, and Pre-AA/Statin (n=7-8/group). On Day 0, to the Pre-AA and Healthy groups, was injected Mycobacterium butyricum or saline, respectively. On Days 4-8, Statin and Placebo groups received either pravastatin (6 mg/kg) or placebo twice daily, respectively. On day 8, heart and blood samples were collected. The density of NET and 1-AR in heart homogenate; NE in plasma and heart and inflammatory mediators (nitrite and interferon-gamma) in serum were determined.
Inflammation was associated with a significant reduction in both beta1-AR and NET density with a positive correlation between the two proteins (r=0.978, p<0.0001). The down-regulating effect of inflammation was not reversed by pravastatin. Inflammation had no significant effect on the plasma or heart NE concentration.
The close relations of NET and beta1-AR implicates altered sympathetic innervation and/or local NE handling in pharmacotherapeutic desensitization observed in arthritis.
类风湿性关节炎和实验性关节炎等形式的炎症不仅会引起关节疼痛，还会导致心血管疾病死亡率过高。这种情况还会降低钙通道和β-肾上腺素能（β1-AR）拮抗剂的反应。对于钙通道抑制剂，反应降低表明靶蛋白的表达减少。羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）可恢复普萘洛尔和维拉帕米的反应。我们测试了佐剂性关节炎对去甲肾上腺素（NE）转运体（NET）密度的影响，因为在类风湿性关节炎中观察到交感神经系统神经支配的改变。
雄性 Sprague-Dawley 大鼠分为以下几组：健康/安慰剂组、健康/他汀组、预佐剂关节炎/安慰剂组和预佐剂关节炎/他汀组（n=7-8/组）。在第 0 天，向预佐剂关节炎组和健康组分别注射分枝杆菌丁酸或生理盐水。在第 4-8 天，他汀组和安慰剂组分别每天两次接受普伐他汀（6mg/kg）或安慰剂。在第 8 天，采集心脏和血液样本。测定心脏匀浆中 NET 和 1-AR 的密度、血浆和心脏中的 NE 以及血清中的炎症介质（亚硝酸盐和干扰素-γ）。
炎症与β1-AR 和 NET 密度均显著降低有关，两种蛋白质之间呈正相关（r=0.978，p<0.0001）。炎症并没有逆转普伐他汀的下调作用。炎症对血浆或心脏 NE 浓度没有显著影响。
NET 和β1-AR 的密切关系提示交感神经支配和/或局部 NE 处理的改变可能与关节炎中观察到的药物治疗脱敏有关。
